Fig. 1. Key targets in the SARS-CoV-2 replication cycle.
a, Stage 1: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell upon binding to the extracellular receptors angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2)119. Stage 2: following viral uncoating, the viral RNA is released and two large open reading frames (ORF1a and ORF1b) are translated into polyproteins. Stage 3: these polyproteins are co- and post-translationally processed by viral proteases into non-structural proteins (NSPs) that form the viral replication complex. Continuous cleavage of the polyprotein is required for sustained RNA synthesis, suggesting that formation of the replication complex is dynamic and occurs continually. Stage 4: the central enzyme of the replication complex is the RNA-dependent RNA polymerase (RdRp), which synthesizes viral RNA. Other enzymes such as the NSP13 helicase and the NSP14 N-methyltransferase contribute to initiation of replication, RNA unwinding, proofreading and sustaining RNA synthesis. Stage 5: genomic viral RNA is encapsulated by nucleocapsid protein (N), and viral structural proteins translocate to the endoplasmic reticulum. Stage 6: structural proteins transit through the endoplasmic reticulum-to-Golgi intermediate compartment (ERGIC) to the Golgi for glycosylation and progression into exocytic vesicles. Encapsidated genomic RNA buds into the final virion, acquiring a lipid bilayer that contains structural proteins spike (S), membrane (M) and envelope (E). Stage 7: the virion is released from the infected cell by exocytosis. Key viral targets are listed in the boxes. b, As part of the innate immune response towards SARS-CoV-2 infection, the host’s pattern recognition receptors such as proteins retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) recognize viral RNA and trigger downstream signalling cascades involving the mitochondrial antiviral signalling protein (MAVS), leading to activation of the IRF3 and nuclear factor-κB (NF-κB) transcription factors that induce interferon-β (IFNβ) transcription. Viral proteins such as those listed in the box interfere with components of the pathway. Mpro, main protease; P, phosphorylation; PLpro, papain-like protease.